This invention relates to a novel polyene antibiotic emulsion formulation suitable for safe, parenteral administration of the polyene antibiotic, and a method for using such formulation.
The polyenes are macrolide antibiotics that selectively inhibit organisms whose membranes contain sterols. They are active against yeast, fungi, and other eukaryotic cells, but have no inhibitory action on the prokaryotic bacteria which lack sterols in their cell membranes. The antifungal activity of the polyenes is due to changes in the permeability of the membrane produced by antibiotic-sterol interaction. For example, treatment of fungal cells with amphotericin B, a polyene antibiotic, produces craters and vesiculation of the plasma membrane, but produces no holes or pores. It is thus believed that the altered permeability is the result of changes in the physical properties of the membranes resulting from avid binding of the polyenes to the membrane sterols which normally stabilize membrane function. The polyene-sterol interaction would then mediate a phase transition from an ordered state to a melted or random state, resulting in increased permeability.
The polyene antibiotic, amphotericin B, remains the cornerstone of antifungal therapy. It is active against most fungi that can cause deep-seated infections. However, even at recommended dosages, in its known parenteral formulations for administration, amphotericin B produces a number of side effects, of which nephrotoxicity is the most serious. Such side effects limit the quantity of amphotericin B which can be safely parenterally administered, and thus also limit the utility of such conventional formulations. Another polyene antifungal agent, nystatin, is also useful clinically. Because of its toxicity when administered parenterally in known formulations, its most important use is in the treatment of topical or superficial infections, especially those caused by Candida. All other known polyene antibiotics are so toxic when administered parenterally that such a delivery route is not viable for administering therapeutic dosages of the antibiotic. Thus, it is clear that there is a real need for the safer, parenteral formulation of this invention which permits administration of conventional or larger dosages of polyene antibiotics, wherein said dosages are toxic in known formulations, without significantly reducing the pharmacologic efficacy of the antibiotic.